This proposal describes a continuing investigation of transition- metal mediated higher-order cycloaddition chemistry and applications to the synthesis of biologically active natural products such as the fungal metabolite, cerorubenol-I and the antitumor ansamycin antibiotic, streptovaricin D. Methodology will be pursued that can be applied to a wide range of medicinally significant macrolide natural products and antitumor sesquiterpene lactone systems. A variety of metal species will be examined for the promotion of efficient [6+4], [6+2] and [5+4] cycloaddition processes. These reactions share a characteristically low level of periselectivity and proceed in very poor chemical yields in the absence of the intervention of a metal center. The concept of transition-metal template control of cycloadditions will be further extended to other promising pathways to establish the general nature of this phenomenon. The development of a catalytic version of these reactions will be pursued as will an extensive investigation of possible avenues for achieving asymmetric induction during the cycloaddition process. A high-level of stereocontrol and a demonstrated capability for rapid assembly of systems exhibiting significant molecular complexity highlight the projected chemistry and render it particularly suitable for construction of the elaborate structural units that are typical of biologically active natural products.